Transdermal delivery system comprising buprenorphine

Abstract

The invention relates to transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid and linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

The invention claimed is: 
     
       1. A method of treating pain in a patient comprising applying a transdermal therapeutic system for the transdermal administration of buprenorphine to the skin of the patient, wherein the transdermal therapeutic system comprises a buprenorphine-containing self-adhesive layer structure comprising
 a. a buprenorphine-impermeable backing layer, and 
 b. a buprenorphine-containing pressure-sensitive adhesive layer on the buprenorphine-impermeable backing layer, the adhesive layer comprising
 i. at least one polymer-based pressure-sensitive adhesive based on polysiloxanes or polyisobutylenes, 
 ii. an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and 
 iii. a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that the analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the pressure-sensitive adhesive,
 wherein the buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer; and wherein the transdermal therapeutic system is applied on the skin of the patient for about 168 hours; 
 
 
 
       wherein the transdermal therapeutic system provides a size of the buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 1 cm 2  to about 4.8 cm 2  and contains an amount of the buprenorphine from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, and 
       wherein the transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg.hr/ml-cm 2  over about 168 hours of administration after a single-dose administration to a subject population. 
     
     
       2. The method of  claim 1 , wherein the transdermal therapeutic system provides a nominal mean release rate of about 5 μg/hr over about 168 hours of administration. 
     
     
       3. The method of  claim 1 , wherein the carboxylic acid is levulinic acid and the polymer-based pressure-sensitive adhesive is based on polysiloxanes. 
     
     
       4. The method of  claim 1 , wherein the transdermal therapeutic system provides a mean AUCt of more than 7,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 
     
     
       5. The method of  claim 1 , wherein the transdermal therapeutic system provides a mean cumulative skin permeation rate of buprenorphine measured in a Franz diffusion cell with dermatomed human skin of more than 1.3 μg/cm 2 -hr over a 168 hours test. 
     
     
       6. The method of  claim 1 , wherein the transdermal therapeutic system provides a cumulative release of buprenorphine as measured in a Franz diffusion cell with dermatomed human skin of 220 μg/cm 2  to 640 μg/cm 2  over a time period of 168 hours. 
     
     
       7. The method of  claim 1 , wherein the transdermal therapeutic system provides a non-cumulative release of buprenorphine as measured in a Franz diffusion cell with dermatomed human skin of
 2 μg/cm 2  to 10 μg/cm 2  in the first 8 hours, 
 20 μg/cm 2  to 80 μg/cm 2  from hour 8 to hour 24, 
 20 μg/cm 2  to 80 μg/cm 2  from hour 24 to hour 32, 
 30 μg/cm 2  to 120 μg/cm 2  from hour 32 to hour 48, 
 40 μg/cm 2  to 150 μg/cm 2  from hour 48 to hour 72, 
 100 μg/cm 2  to 300 μg/cm 2  from hour 72 to hour 144, and 
 30 μg/cm 2  to 100 μg/cm 2  from hour 144 to hour 168. 
 
     
     
       8. A method of treating pain in a patient comprising applying a transdermal therapeutic system for the transdermal administration of buprenorphine to the skin of the patient, wherein the transdermal therapeutic system comprises a buprenorphine-containing self-adhesive layer structure comprising
 a. a buprenorphine-impermeable backing layer, and 
 b. a buprenorphine-containing pressure-sensitive adhesive layer on the buprenorphine-impermeable backing layer, the adhesive layer comprising
 i. at least one polymer-based pressure-sensitive adhesive based on polysiloxanes or polyisobutylenes, 
 ii. an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and 
 iii. a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that the analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the pressure-sensitive adhesive,
 wherein the buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer; and wherein the transdermal therapeutic system is applied on the skin of the patient for about 168 hours; 
 
 
 
       wherein the transdermal therapeutic system provides a size of the buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 3 cm 2  to about 9.5 cm 2  and contains an amount of the buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, and 
       wherein the transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg.hr/ml-cm 2  over about 168 hours of administration after a single-dose administration to a subject population. 
     
     
       9. The method of  claim 8 , wherein the transdermal therapeutic system provides a nominal mean release rate of about 10 μg/hr over about 168 hours of administration. 
     
     
       10. The method of  claim 8 , wherein the carboxylic acid is levulinic acid and the polymer-based pressure-sensitive adhesive is based on polysiloxanes. 
     
     
       11. The method of  claim 8 , wherein the transdermal therapeutic system provides a mean AUCt of more than 14,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 
     
     
       12. The method of  claim 8 , wherein the transdermal therapeutic system provides a mean cumulative skin permeation rate of buprenorphine measured in a Franz diffusion cell with dermatomed human skin of more than 1.3 μg/cm 2 -hr over a 168 hours test. 
     
     
       13. The method of  claim 8 , wherein the transdermal therapeutic system provides a cumulative release of buprenorphine as measured in a Franz diffusion cell with dermatomed human skin of 220 μg/cm 2  to 640 μg/cm 2  over a time period of 168 hours. 
     
     
       14. The method of  claim 8 , wherein the transdermal therapeutic system provides a non-cumulative release of buprenorphine as measured in a Franz diffusion cell with dermatomed human skin of
 2 μg/cm 2  to 10 μg/cm 2  in the first 8 hours, 
 20 μg/cm 2  to 80 μg/cm 2  from hour 8 to hour 24, 
 20 μg/cm 2  to 80 μg/cm 2  from hour 24 to hour 32, 
 30 μg/cm 2  to 120 μg/cm 2  from hour 32 to hour 48, 
 40 μg/cm 2  to 150 μg/cm 2  from hour 48 to hour 72, 
 100 μg/cm 2  to 300 μg/cm 2  from hour 72 to hour 144, and 
 30 μg/cm 2  to 100 μg/cm 2  from hour 144 to hour 168. 
 
     
     
       15. A method of treating pain in a patient comprising applying a transdermal therapeutic system for the transdermal administration of buprenorphine to the skin of the patient, wherein the transdermal therapeutic system comprises a buprenorphine-containing self-adhesive layer structure comprising
 a. a buprenorphine-impermeable backing layer, and 
 b. a buprenorphine-containing pressure-sensitive adhesive layer on the buprenorphine-impermeable backing layer, the adhesive layer comprising
 i. at least one polymer-based pressure-sensitive adhesive based on polysiloxanes or polyisobutylenes, 
 ii. an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and 
 iii. a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that the analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the pressure-sensitive adhesive,
 wherein the buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer; and wherein the transdermal therapeutic system is applied on the skin of the patient for about 168 hours; 
 
 
 
       wherein the transdermal therapeutic system provides a size of the buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 6 cm 2  to about 14 cm 2  and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, and 
       wherein the transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg.hr/ml-cm 2  over about 168 hours of administration after a single-dose administration to a subject population. 
     
     
       16. The method of  claim 15 , wherein the transdermal therapeutic system provides a nominal mean release rate of about 20 μg/hr over about 168 hours of administration. 
     
     
       17. The method of  claim 15 , wherein the carboxylic acid is levulinic acid and the polymer-based pressure-sensitive adhesive is based on polysiloxanes. 
     
     
       18. The method of  claim 15 , wherein the transdermal therapeutic system provides a mean AUCt of more than 28,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 
     
     
       19. The method of  claim 15 , wherein the transdermal therapeutic system provides a mean cumulative skin permeation rate of buprenorphine measured in a Franz diffusion cell with dermatomed human skin of more than 1.3 μg/cm 2 -hr over a 168 hours test. 
     
     
       20. The method of  claim 15 , wherein the transdermal therapeutic system provides a cumulative release of buprenorphine as measured in a Franz diffusion cell with dermatomed human skin of 220 μg/cm 2  to 640 μg/cm 2  over a time period of 168 hours. 
     
     
       21. The method of  claim 15 , wherein the transdermal therapeutic system provides a non-cumulative release of buprenorphine as measured in a Franz diffusion cell with dermatomed human skin of
 2 μg/cm 2  to 10 μg/cm 2  in the first 8 hours, 
 20 μg/cm 2  to 80 μg/cm 2  from hour 8 to hour 24, 
 20 μg/cm 2  to 80 μg/cm 2  from hour 24 to hour 32, 
 30 μg/cm 2  to 120 μg/cm 2  from hour 32 to hour 48, 
 40 μg/cm 2  to 150 μg/cm 2  from hour 48 to hour 72, 
 100 μg/cm 2  to 300 μg/cm 2  from hour 72 to hour 144, and 
 30 μg/cm 2  to 100 μg/cm 2  from hour 144 to hour 168. 
 
     
     
       22. A method of treating pain in a patient comprising applying a transdermal therapeutic system for the transdermal administration of buprenorphine to the skin of the patient, wherein the transdermal therapeutic system comprises a buprenorphine-containing self-adhesive layer structure comprising
 a. a buprenorphine-impermeable backing layer, and 
 b. a buprenorphine-containing pressure-sensitive adhesive layer on the buprenorphine-impermeable backing layer, the adhesive layer comprising
 i. at least one polymer-based pressure-sensitive adhesive based on polysiloxanes or polyisobutylenes, 
 ii. an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and 
 iii. a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that the analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the pressure-sensitive adhesive,
 wherein the buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer; and wherein the transdermal therapeutic system is applied on the skin of the patient for about 168 hours; 
 
 
 
       wherein the transdermal therapeutic system provides a size of the buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 12 cm 2  to about 28.5 cm 2  and contains an amount of the buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, and 
       wherein the transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg.hr/ml-cm 2  over about 168 hours of administration after a single-dose administration to a subject population. 
     
     
       23. The method of  claim 22 , wherein the transdermal therapeutic system provides a nominal mean release rate of about 30 μg/hr over about 168 hours of administration. 
     
     
       24. The method of  claim 22 , wherein the carboxylic acid is levulinic acid and the polymer-based pressure-sensitive adhesive is based on polysiloxanes. 
     
     
       25. The method of  claim 22 , wherein the transdermal therapeutic system provides a mean AUCt of more than 42,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 
     
     
       26. The method of  claim 22 , wherein the transdermal therapeutic system provides a mean cumulative skin permeation rate of buprenorphine measured in a Franz diffusion cell with dermatomed human skin of more than 1.3 μg/cm 2 -hr over a 168 hours test. 
     
     
       27. The method of  claim 22 , wherein the transdermal therapeutic system provides a cumulative release of buprenorphine as measured in a Franz diffusion cell with dermatomed human skin of 220 μg/cm 2  to 640 μg/cm 2  over a time period of 168 hours. 
     
     
       28. The method of  claim 22 , wherein the transdermal therapeutic system provides a non-cumulative release of buprenorphine as measured in a Franz diffusion cell with dermatomed human skin of
 2 μg/cm 2  to 10 μg/cm 2  in the first 8 hours, 
 20 μg/cm 2  to 80 μg/cm 2  from hour 8 to hour 24, 
 20 μg/cm 2  to 80 μg/cm 2  from hour 24 to hour 32, 
 30 μg/cm 2  to 120 μg/cm 2  from hour 32 to hour 48, 
 40 μg/cm 2  to 150 μg/cm 2  from hour 48 to hour 72, 
 100 μg/cm 2  to 300 μg/cm 2  from hour 72 to hour 144, and 
 30 μg/cm 2  to 100 μg/cm 2  from hour 144 to hour 168.